The long-term objective of this program is to improve treatment of brain tumors by further implementing our novel approach of controlled delivery of effective agents directly to the site of the tumor via biodegradable polymers. Through the collaborative efforts of this NCDDG, we developed therapeutic applications for new polymer-drug combinations, and established their biocompatibility, safety, and effectiveness in a series of preclinical studies. These studies led to the development of Gliadel, a polymer-based chemotherapy for malignant gliomas, now approved worldwide and also the first FDA-approved treatment for brain tumors in 23 years; 28 additional clinical trials, including 3 funded by the NCI, are currently building on these initial advances. The proof of principle from these studies has substantiated our use of agents that may be significantly more effective in treating cancer. We can now build on the extensive work that has been accomplished over the last 9 years. We will test the hypothesis that direct delivery of an effective agent to a tumor will improve outcome and minimize systemic toxicity, and that in particular, combinations of therapeutic agents and or biological approaches will be more effective than single agents. Our specific aims are: Aim 1: To test effectiveness of new biodegradable polymers by (a) evaluating their safety in the brain; and (b) assessing their effectiveness when utilized with established drugs against rat brain tumors. Aim 2: To test effectiveness of newly developed anti-tumor drugs by (a) determining their release kinetics from various polymers and their efficacy in vitro; (b) evaluating new drug polymer combinations for neurotoxicity and effectiveness in the rat 9L glioma model. We will further evaluate drugs that showed great potential from the last funding period including: paclitaxel, camptothecin analogs, resistance modifiers, and cytokines. Aim 3: To explore combinations of drugs and other treatments, including (a) investigating resistance modifiers in combination with chemotherapy; and (b) using cytokines, anti-angiogenic agents, and monoclonal antibodies with chemotherapeutic agents.